Approximately 500,000 new cases of head and neck squamous cell carcinoma (HNSCC), including the oral cavity, pharynx and larynx, are reported each year. Compelling evidence exists for a dysplasia- carcinoma sequence for HNSCC whereby a series of genetic 'hits'are required to allow cells to progress through hyperplasia, dysplasia, carcinoma in situ, invasive tumor, and metastatic tumor. Genetic instability is the sine qua non of most epithelial cancers with HNSCC following form. Similar to other forms of epithelial neoplasia such as colon cancer, genetic instability measured by loss of heterozygosity (allelic imbalance) is an early carcinogenic event in the epithelium lining the aerodigestive tract, and may be a key driving force in the emergence of clonal populations. The ability to recognize and detect the progression of genetic events occurring in the epithelium lining of the aerodigestive tract during tumorigenesis is critical to developing strategies for therapeutic intervention. We propose to use a discovery-driven approach to perform a comprehensive, genome-wide analysis of dysplasia of the oral cavity and HNSCC in our effort to identify and validate these genetic events. We will examine cases of precursor lesions or dysplasia (phenotypically observed as oral leukoplakia), early stage disease (primary tumor, no cervical lymph node metastases) and late stage (primary tumor and cervical lymph node metastases with/without distant metastases) for genomic copy number changes using BAG array based Comparative Genomic Hybridization (aCGH). We have developed this approach and demonstrated its effectiveness in identifying copy number changes. Our intent is to identify a set of biomarkers, observed as genomic copy number aberrations, that can be used for early disease detection and monitoring for recurrent disease. Clearly, the analysis will also lead to a better understanding of the genetic events leading to invasive HNSCC.